EMP3 mediates glioblastoma‐associated macrophage infiltration to drive T cell exclusion

Abstract

Background: The immunosuppressive tumour microenvironment is a critical factor in the initiation and progression of glioblastoma (GBM), which is characterized by an abundance of tumour-associated macrophages (TAMs) but a paucity of infiltrating T cells. In this research, we studied whether epithelial membrane protein 3 (EMP3) plays a crucial role in immune modulation in GBM. Methods: TCGA and CGGA transcriptomic profiles of wild-type IDH1 GBM were used for bioinformatic analysis. The role of EMP3 in GBM was validated through in vivo and in vitro experiments. Human GBM specimens were collected and evaluated using immunofluorescence analysis. Results: EMP3 was associated with immunosuppression in GBM. Elevated EMP3 in GBM areas was accompanied by high expression of PD-L1 and abundant M2 TAM recruitment but a lake of T cell infiltration. We found that EMP3 was a potent protein in M2 TAM polarization and recruitment that impaired the ability of GBM cells to secrete CCL2 and TGF-β1. Furthermore, EMP3 suppressed T cell infiltration into GBM tumours by inhibiting the secretion of CXCL9 and CXCL10 by macrophages and led to an effective response to anti-PD1 therapy. Conclusions: EMP3 is thus a critical immunosuppressive factor for recruiting TAMs in GBM and suppressing intratumoural T cell infiltration to facilitate tumour progression and is a potential therapeutic target.